The immune system distinguishes self from non-self. In autoimmunity, this ability fails. My research concentrates on the systemic autoimmune diseases, systemic lupus erythematosus and Sjögren's syndrome, which are characterized by a loss of tolerance to the ubiquitous antigens Ro/SSA and La/SSB. We use a wide range of scientific disciplines, from clinical research to laboratory-based basic research to animal models of human disease.

Presently we are studying a powerful genetic association on chromosome 11 at p13 that was originally found in families with severe SLE that are ethnically identified as Black Americans. High density single nucleotide polymorphism typing has identified a highly promising candidate gene, which is now being pursued with studies designed to explore the mechanism by which SLE susceptibility is increased. The etiology for the preponderance of women with SLE is under study. We have found that Klinefelter's syndrome (male 47, XXY) is found in excess among men with SLE, while 47,XXX is increased among women with SLE. Genetic linkage on X is established and is being further defined to test the hypothesis of a gene dose effect. Other genetic interests include the relationship of prolidase deficiency to systemic autoimmunity, and the genetics of Sjögren's syndrome. We are in the process of finalizing the first genome-wide association study for this disease.

My laboratory is also interested in the immunology of systemic lupus erythematosus and Sjögren's syndrome. Immunization of animals with short peptides from 60 kD Ro induces epitope spreading as well as a Sjögren's syndrome-like illness. The immunology and genetics of this model are being explored. Future studies of this model include adoptive transfer, genetic control of epitope spreading as well as disease manifestations, MRI imaging of animals, and prevention by dendritic cell immunization. This project complements animal immunization studies in which oxidatively modified antigens induce enhanced epitope spreading and disease. We also find that humans with SLE have more oxidative modification of proteins and lipids than do controls.

Human lupus and Sjögren's are being studied at the level of B cell immunity. We have found that transfer of anti-Ro antibodies into naïve animals induces salivary gland dysfunction. The mechanism of this pathology is being investigated, including in 60 kD Ro knock out animals.

Clinical research involving diabetes among patients with lupus is ongoing. In addition, clinical research is being pursued in a comprehensive Sjögren's syndrome research clinic in which patients undergo a complete dental, ophthalmological, and medical evaluation.

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